The present invention relates to a serotonin reuptake inhibitor. The serotonin reuptake inhibitor of the present invention is a selective serotonin reuptake inhibitor that has affinity for serotonin 1A receptors, has a small inhibitory effect on the reuptake of dopamine and noradrenaline, and strongly inhibits serotonin reuptake. In addition, the present invention relates to a novel compound having such a selective inhibitory effect on serotonin reuptake. Furthermore, the present invention relates to a novel benzylpiperidine derivative that is an intermediate for synthesizing such a compound, and a process for producing the derivative.
Depression is a chronic disease that affects persons of all ages. Of various antidepressants used at present, the most successful antidepressants are selective serotonin reuptake inhibitors (hereinafter abbreviated as SSRI in some cases). SSRI has serotonin reuptake inhibitory effect more selective than dopamine and noradrenaline reuptake inhibitory effect. The first drug put on the market as SSRI is zimelidine. Other SSRIs that have been put on the market or are under development include, for example, fluoxetine, fluvoxamine, citalopram, cericlamine, femoxetine, ifoxetine, cyanodothiepin, sertraline, paroxetine and lotoxetine.
Although SSRIs are the most successful as antidepressants at present, several problems in them are pointed out. Of these problems, the following two problems are typical: about one-third of all melancholiacs are so difficult to cure that SSRIs are not sufficiently effective, and the exhibition of a sufficient clinical effect of SSRI requires 3 to 8 weeks. In particular, this slow exhibition of antidepressant effect causes the following problems. Since side effects are brought about immediately though the exhibition of antidepressant effect is slow, there is a vulnerable period in which the patient undergoes only the side effects without obtaining the therapeutic effect of the drug. Therefore, persuading the patient into continuing the same treatment also in this period is often a heavy burden for a doctor in charge. In addition, because of the gradual beginning of experience of the effect, a patient who tends to commit suicide resumes initiative before experiencing sufficient improvement of depressive condition. Therefore, there are, for example, a risk of suicide and a necessity for frequent admission into a hospital. Accordingly, the development of an antidepressant capable of exhibiting its effect rapidly is desired.
The reason why the exhibition of the antidepressant effect of SSRI requires several weeks is as follows.
SSRI inhibits rapid serotonin reuptake in serotonin metabolic turnover. Since this action takes place at the nerve ending of each serotonergic neuron, neurotransmission due to serotonin is enhanced. The inhibition of rapid serotonin reuptake by SSRI, however, takes place also in serotonergic neuron cell bodies and dendrites, which are present in raphe nucleus. Therefore, the firing auto-inhibition (the negative feedback reaction) of the serotonergic neuron through 5-HT1A auto-receptor is also enhanced in the raphe nucleus. As a result, the neurotransmission in the serotonergic neuron is not enhanced to an expected degree as a whole by initial administration of SSRI. On the other hand, in the course of continuous taking of SSRI for several weeks, serotonin 1A auto-receptors present on serotonergic neuronal cell bodies and dendrites in the raphe nucleus are desensitized, so that the negative feed back reaction is abolished. As a result, the firing inhibition of the serotonergic neuron is broken down, so that the enhancement of the activity of the serotonergic neuron and the inhibition of serotonin uptake at the nerve ending succeed cooperatively. Therefore, the serotonin neurotransmission is enhanced, resulting in exhibition of the antidepressant effect.
Accordingly, the reduction of a period required for the exhibition of the effect of SSRI or the enhancement of the antidepressant effect can be achieved either by stopping the negative feedback reaction of serotonin by inhibiting the serotonin 1A auto-receptor by the use of a serotonin 1A receptor antagonist, or by reducing a period required for the desensitization by positively stimulating the serotonin 1A auto-receptor by the use of a serotonin 1A receptor agonist. That is, a compound having affinity for serotonin 1A receptors and a selective inhibitory effect on serotonin reuptake has a marked antidepressant effect and hence can be used as a therapeutic agent for psychiatric diseases which exhibits its effect after a reduced period. In fact, it has been reported that, for example, pindolol having a high affinity for serotonin 1A receptors increases the effect of a serotonin reuptake inhibitor in a melancholiac and reduces a period required for the onset of the effect (Arch, Gen. Psychiatry, (1994), 51, 248-251).
There are many references concerning nitrogen-containing saturated heterocyclic derivatives substituted by a benzyl group which include nitrogen-containing saturated heterocyclic derivatives substituted by an N-aralkyl group and a benzyl group. As to the nitrogen-containing saturated heterocyclic derivatives substituted by an N-aralkyl group and a benzyl group, Arch. Pharm. (Weinheim, Ger.)(1979), 312, 670-681, for example, describes benzylpiperidine derivatives having psychotropic effect like dopamine. Japanese Patent No. 2573195 discloses cyclic amine derivatives as therapeutic agents for psychiatric symptoms accompanying a cerebrovascular accident. Med. Chem. Res. (1992), 2, 368-375 describes N-aralkyl-substituted 4-benzylpiperidines as sigma receptor ligands. International Publication No. WO 93/97216 discloses N-aralkyl-substituted 4-benzylpiperidines as NMDA receptor antagonists. None of these prior art references, however, report that the compounds described therein have inhibitory effect on serotonin reuptake. As 4-benzylpiperidines substituted by a substituted alkyl group having a heterocyclic group as the substituent, there are compounds disclosed in JP-A-63-183576. This reference, however, does not report either that these substituted 4-benzylpiperidines have inhibitory effect on serotonin reuptake. In addition, as 4-benzylpiperidines substituted by a cycloalkylalkyl group, there are the compounds disclosed in DE3614907. This reference, however, does not report either that these substituted 4-benzylpiperidines have inhibitory effect on serotonin reuptake.
Various derivatives have been known as only nitrogen-containing saturated heterocyclic derivatives substituted by a substituted benzyl group, in particular, 4-substituted benzylpiperidines. For example, J. Org. Chem. (1999), 64, 3763-3766 and CA2188485 disclose synthesis processes of the derivatives. Neither of these prior art references, however, reports a 2-substituted benzylpiperidine containing a bromine atom. Moreover, this compound cannot be synthesized according to the disclosed process.
The present invention is intended to provide a selective serotonin reuptake inhibitor having affinity for serotonin 1A receptors. Specifically, the present invention is intended to provide a selective serotonin reuptake inhibitor having affinity for serotonin 1A receptors which is useful as a therapeutic agent for mood disorders including depression, seasonal affective disorder and dysthymia in human beings and animals; anxiety disorders including generalized anxiety disorder, obsessive-compulsive disorder and panic disorder; agoraphobia and avoidant personality disorder; social phobia; compulsive reaction; post-traumatic stress disorder; psychosomatic disorder; retention defects including dementia, forgetfulness and retention defect associated with aging; eating disorders including anorexia nervosa and bulimia nervosa; obesity; somnipathy; schizophrenia; chemical dependency due to alcohol, tobacco, nicotine or the like; cluster headache; migraine; pains; Alzheimer""s disease; chronic paroxysmal migraine; headache associated with vasculopathy; Parkinson""s disease including dementia, depression and anxiety caused by Parkinson""s disease, Parkinsonism induced by a neuroleptic agent, and tardive dyskinesia; dysendocrinism such as hyperprolactinemia; vasospasm (in particular, cerebrovascular spasm); hypertension; kinetic gastrointestinal troubles and gastrointestinal troubles in which a secretion change participates; sexual dysfunction including premature ejaculation; and drug dependence. Furthermore, the present invention is intended to provide novel benzylpiperidine derivatives useful as intermediates of medicines and agrochemicals, which include compounds having a selective inhibitory effect on serotonin reuptake.
The present invention relates to the following items [1] to [25].
[1]. A serotonin reuptake inhibitor comprising a cyclic amine represented by the formula (1): 
wherein R0 is a hydrogen atom, a halogen atom, an alkyl group, a substituted alkyl group, a hydroxyl group, an alkoxy group, a substituted alkoxy group, an alkylthio group or a substituted alkylthio group, provided that when two or more R0s are present, they are independently selected from the above-mentioned groups or two of them may be taken together to form a ring;
R3 is a hydrogen atom or a substituent;
Y is a group represented by the formula: 
Z is a hydrogen atom, a cycloalkyl group, an aryl group, a substituted aryl group, an aromatic heterocyclic group, a substituted aromatic heterocyclic group, or an aliphatic heterocyclic group having an amide linkage (COxe2x80x94N) or an imide linkage (COxe2x80x94Nxe2x80x94CO) in the ring;
n is an integer of 1, 2 or 3;
m is an integer of 2, 3, 4, 5 or 6;
R5s are independently a hydrogen atom or a substituent; and
R6s are independently a hydrogen atom or a substituent,
a prodrug of said cyclic amine, or a pharmaceutically acceptable salt of said cyclic amine or prodrug, as an active ingredient.
[2]. A serotonin reuptake inhibitor according to the above item [1], which comprises a cyclic amine represented by the formula: 
wherein R1 is a halogen atom, an alkyl group or a substituted alkyl group;
R2 is a hydrogen atom, a hydroxyl group, an alkoxy group, a substituted alkoxy group, an alkylthio group, a substituted alkylthio group or a halogen atom, provided that R1 is a bromine atom in the case of R2 being a hydrogen atom;
R4 is a hydrogen atom, a halogen atom or an alkoxy group, or R4 may be taken together with R2 to form a ring; and
R3, Y, Z and n are as defined in the above item [1],
a prodrug of said cyclic amine, or a pharmaceutically acceptable salt of said cyclic amine or prodrug, as an active ingredient.
[3]. A serotonin reuptake inhibitor according to the above item [2], wherein R1 is a halogen atom or a lower alkyl group.
[4]. A serotonin reuptake inhibitor according to the above item [2] or [3], wherein R2 is a hydroxyl group, a lower alkoxy group or a halogen atom.
[5]. A serotonin reuptake inhibitor according to any one of the above items [2] to [4], wherein R3 is a hydrogen atom or a lower alkyl group.
[6]. A serotonin reuptake inhibitor according to any one of the above items [2] to [5], wherein m is 2 or 3.
[7]. A serotonin reuptake inhibitor according to any one of the above items [2] to [6], wherein n is 1 or 2.
[8]. A serotonin reuptake inhibitor according to any one of the above items [2] to [7], wherein Z is a cycloalkyl group.
[9]. A cyclic amine represented by the formula: 
wherein R1 is a halogen atom or a lower alkyl group;
R2 is a hydroxyl group, a lower alkoxy group, a substituted lower alkoxy group or a halogen atom, provided that R1 and R2 are not the same;
R3 is a hydrogen atom or a lower alkyl group;
R4 is a hydrogen atom, a halogen atom or a lower alkoxy group, or R4 may be taken together with R2 to form a ring;
n is an integer of 1 or 2; and
Y and Z are as defined in the above item [1], a prodrug of said cyclic amine, or a pharmaceutically acceptable salt of said cyclic amine or prodrug.
[10]. A cyclic amine represented by the formula: 
wherein R1 is a halogen atom or a lower alkyl group;
R2 is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a substituted lower alkoxy group or a halogen atom, provided that R1 is a bromine atom in the case of R2 being a hydrogen atom;
R3 is a hydrogen atom or a lower alkyl group;
R4 is a hydrogen atom, a halogen atom or a lower alkoxy group, or R4 may be taken together with R2 to form a ring;
n is an integer of 1 or 2; and
Y and Z are as defined in the above item [1], a prodrug of said cyclic amine, or a pharmaceutically acceptable salt of said cyclic amine or prodrug.
[11]. A compound according to the above item [9] or [10], wherein Z is a phenyl group or a substituted phenyl group.
[12]. A compound according to the above item [9] or [10], wherein Z is a substituted phenyl group having 1 to 3 substituents which may be the same or different and are selected from halogen atoms, lower alkoxy groups (which may form a ring as substituents on adjacent carbon atoms), carbamoyl group, N-substituted carbamoyl groups and N,N-di-substituted carbamoyl groups.
[13]. A compound according to any one of the above items [9] to [12], wherein m is 2.
[14]. A compound according to any one of the above items [9] to [13], wherein each of R5 and R6 is a hydrogen atom.
[15]. A compound according to any one of the above items [9] to [14], wherein R1 is a bromine atom, a chlorine atom, a methyl group or an ethyl group.
[16]. A compound according to any one of the above items [9] to [15], wherein R2 is a lower alkoxy group or a halogen atom.
[17]. A compound according to the above item [9] or [10], wherein Z is a cycloalkyl group.
[18]. A compound according to the above item [17], wherein R1 is a bromine atom, a chlorine atom, a methyl group or an ethyl group.
[19]. A compound according to the above item [17] or [18], wherein R2 is a lower alkoxy group or a halogen atom.
[20]. Any compound selected from the group consisting of the following compounds (1) to (40), a pharmacologically acceptable salt thereof, or a solvate of said compound or salt:
(1) N-benzyl-3-{2-[4-(2-bromo-5-methoxybenzyl)-1-piperidinyl]ethyl}benzamide,
(2) 3-{2-[4-(2-bromo-5-methoxybenzyl)-1-piperidinyl]ethyl}benzamide,
(3) 3-{2-[4-(2-bromo-5-ethoxybenzyl)-1-piperidinyl]ethyl}benzamide,
(4) 3-{2-[4-(2-bromo-5-isopropoxybenzyl)-1-piperidinyl]ethyl}benzamide,
(5) 3-{2-[4-(2-bromo-5-methoxybenzyl)-1-piperidinyl]ethyl}-N,N-dimethylbenzamide,
(6) 3-{2-[4-(2-bromo-5-ethoxybenzyl)-1-piperidinyl]ethyl}-N,N-dimethylbenzamide,
(7) 3-{2-[4-(2-bromo-5-isopropoxybenzyl)-1-piperidinyl]ethyl}-N,N-dimethylbenzamide,
(8) 3-{2-[4-(2-bromo-5-chlorobenzyl)-1-piperidinyl]ethyl}-N,N-dimethylbenzamide,
(9) 3-{2-[4-(2-bromo-5-fluorobenzyl)-1-piperidinyl]ethyl}-N,N-dimethylbenzamide,
(10) 4-(2-bromo-5-methoxybenzyl)-1-[2-(2-chlorophenyl)ethyl]piperidine,
(11) 4-(2-bromo-5-ethoxybenzyl)-1-[2-(2-chlorophenyl)ethyl]piperidine,
(12) 4-(2-bromo-5-isopropoxybenzyl)-1-[2-(2-chlorophenyl)ethyl]piperidine,
(13) 4-(2-bromo-5-methoxybenzyl)-1-[2-(2-methoxyphenyl)ethyl]piperidine,
(14) 4-(2-bromo-5-methoxybenzyl)-1-[2-(2-ethoxyphenyl)ethyl]piperidine,
(15) 4-(2-bromo-5-methoxybenzyl)-1-[2-(3-methoxyphenyl)ethyl]piperidine,
(16) 4-(2-bromo-5-methoxybenzyl)-1-[2-(3-isopropoxyphenyl)ethyl]piperidine,
(17) 4-(2-bromo-5-chlorobenzyl)-1-[2-(3-methoxyphenyl)ethyl]piperidine,
(18) 4-(2-bromo-5-chlorobenzyl)-1-[2-(3-ethoxyphenyl)ethyl]piperidine,
(19) 4-(2-bromo-5-chlorobenzyl)-1-[2-(3-isopropoxyphenyl)ethyl]piperidine,
(20) 4-(2-bromo-5-fluorobenzyl)-1-[2-(3-methoxyphenyl)ethyl]piperidine,
(21) 4-(2-bromo-5-fluorobenzyl)-1-[2-(3-ethoxyphenyl)ethyl]piperidine,
(22) 4-(2-bromo-5-fluorobenzyl)-1-[2-(3-isopropoxyphenyl)ethyl]piperidine,
(23) 4-(2-bromo-5-methoxybenzyl)-1-[2-(2-chloro-6-fluorophenyl)ethyl]piperidine,
(24) 1-[2-(1,3-benzodioxol-5-yl)ethyl]-4-(2-bromo-5-methoxybenzyl)piperidine,
(25) 1-[2-(1,3-benzodioxol-5-yl)ethyl]-4-(2-bromo-5-ethoxybenzyl)piperidine,
(26) 1-[2-(1,3-benzodioxol-5-yl)ethyl]-4-(2-bromo-5-isopropoxybenzyl)piperidine,
(27) 1-[2-(1,3-benzodioxol-5-yl)ethyl]-4-(2-bromo-5-fluorobenzyl)piperidine,
(28) 1-[2-(1,3-benzodioxol-5-yl)ethyl]-4-(2-bromo-5-chlorobenzyl)piperidine,
(29) 4-(2-bromo-5-methoxybenzyl)-1-[2-(6-chloro-1,3-benzodioxol-5-yl)ethyl]piperidine,
(30) 4-(2-bromo-5-ethoxybenzyl)-1-[2-(6-chloro-1,3-benzodioxol-5-yl)ethyl]piperidine,
(31) 4-(2-bromo-5-isopropoxybenzyl)-1-[2-(6-chloro-1,3-benzodioxol-5-yl)ethyl]piperidine,
(32) 4-(2-bromo-5-chlorobenzyl)-1-[2-(6-chloro-1,3-benzodioxol-5-yl)ethyl]piperidine,
(33) 4-(2-bromo-5-fluorobenzyl)-1-[2-(6-chloro-1,3-benzodioxol-5-yl)ethyl]piperidine,
(34) 4-(2-bromo-5-methoxybenzyl)-1-[2-(2-chloro-3-methoxyphenyl)ethyl]piperidine,
(35) 4-(2-bromo-5-fluorobenzyl)-1-[2-(2-chloro-4-methoxyphenyl)ethyl]piperidine,
(36) 4-(2-bromo-5-methoxybenzyl)-1-[2-(2-naphthyl)ethyl]piperidine,
(37) 4-(2-bromo-5-methoxybenzyl)-1-[2-(4-fluorophenyl)ethyl]piperidine,
(38) 4-benzyl-2-{4-[4-(5-methoxy-2-methylbenzyl)-1-piperidinyl]butyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one,
(39) 4-benzyl-2-{4-[4-(2-bromo-5-methoxybenzyl)-1-piperidinyl]butyl}-1,2,4-triazine-3,5(2H,4H)-dione, and
(40) 2-{3-[4-(2-bromo-5-methoxybenzyl)-1-piperidinyl]propyl}-1H-isoindole-1,3(2H)-dione.
[21]. A cyclic amine represented by the formula: 
wherein R1 is a bromine atom, a chlorine atom or a lower alkyl group;
R2 is a hydroxyl group, a lower alkoxy group, a substituted lower alkoxy group or a halogen atom;
R3 is a hydrogen atom or a lower alkyl group;
R4 is a hydrogen atom, a halogen atom or an alkoxy group, or R4 may be taken together with R2 to form a ring; and
n is an integer of 1 or 2, or
a salt of said cyclic amine.
[22]. A cyclic amine represented by the formula: 
wherein R1 is a bromine atom, a chlorine atom or a lower alkyl group;
R2 is a hydroxyl group, a lower alkoxy group, a substituted lower alkoxy group or a halogen atom, provided that R1 and R2 are not chlorine atoms at the same time;
R3 is a hydrogen atom or a lower alkyl group;
R4 is a hydrogen atom, a halogen atom or an alkoxy group, or R4 may be taken together with R2 to form a ring; and
n is an integer of 1 or 2, or
a salt of said cyclic amine.
[23]. Any compound selected from the group consisting of the following compounds (1) to (16), a salt thereof, or a solvate of said compound or salt:
(1) 4-(2-bromo-5-methoxybenzyl)piperidine,
(2) 4-(2-bromo-5-hydroxybenzyl)piperidine,
(3) 4-(2-bromo-5-ethoxybenzyl)piperidine,
(4) 4-(2-bromo-5-isopropoxybenzyl)piperidine,
(5) 4-[2-bromo-5-(difluoromethoxy)benzyl]-piperidine,
(6) 4-(2-bromo-5-fluorobenzyl)piperidine,
(7) 4-(2-bromo-5-chlorobenzyl)piperidine,
(8) 4-[(6-bromo-1,3-benzodioxol-5-yl)methyl]-piperidine,
(9) 4-(2-chloro-5-methoxybenzyl)piperidine,
(10) 4-(2-chloro-5-hydroxybenzyl)piperidine,
(11) 4-(2-chloro-5-ethoxybenzyl)piperidine,
(12) 4-(2-chloro-5-isopropoxybenzyl)piperidine,
(13) 4-[2-chloro-5-(difluoromethoxy)benzyl]-piperidine,
(14) 4-(2-chloro-5-fluorobenzyl)piperidine,
(15) 4-(2-chloro-5-chlorobenzyl)piperidine, and
(16) 4-[(6-chloro-1,3-benzodioxol-5-yl)methyl]-piperidine.
[24]. A process for producing a compound represented by the formula: 
which comprises reducing a compound represented by the formula: 
to obtain a compound represented by the formula: 
and then removing a protective group (in the above formulas, R1, R2, R3, R4 and n are as defined in the above item [21], and PG is a protective group for nitrogen).
[25]. A process for producing a compound represented by the formula: 
which comprises
1) reacting a compound represented by the formula: 
with a compound represented by the formula (3): Xxe2x80x94Yxe2x80x94Z; or
2) reacting the former compound with a carboxylic acid compound represented by the formula (4): HOOCxe2x80x94Y1xe2x80x94Z, and then reducing the amide linkage; or
3) reacting the former compound with an aldehyde compound represented by the formula (6): OHCxe2x80x94Y1xe2x80x94Z under reductive amination conditions (in the above formulas, R1, R2, R3, R4, Y, Z and n are as defined in the above item [9], X is a leaving group, Y1 is a substituted or unsubstituted alkylene group having a carbon atom(s) in a number smaller by one than the number of carbon atoms of Y, and xe2x80x94CH2xe2x80x94Y1xe2x80x94 corresponds to Y).
The groups in the present invention are concretely explained below.
One or more groups R0 s may be present. When two or more groups R0 s are present, they are independently selected from the above-mentioned groups. The case where two groups R0 s are taken together to form a ring is, for example, the case where two groups R0 s are taken together to form an alkylenedioxy group of two or less carbon atoms, such as methylenedioxy.
The halogen atom includes, for example, bromine atom, chlorine atom and fluorine atom.
The alkyl group includes, for example, alkyl groups of 10 or less carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-ethylpropyl, hexyl, heptyl, octyl, etc. Preferable examples of the alkyl group are methyl, ethyl, propyl and isopropyl.
The lower alkyl group includes, for example, alkyl groups of 6 or less carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-ethylpropyl, hexyl, etc. Especially preferable examples of the lower alkyl group are methyl, ethyl, propyl and isopropyl.
The substituent(s) of each of the substituted alkyl group and the substituted lower alkyl group includes, for example, halogen atoms (which may be present on the same carbon atom in a number of 1 to 3 as the substituent(s)), hydroxyl group, alkoxy groups, aryl groups (e.g. phenyl group), substituted aryl groups, phenoxy group and cycloalkyl groups.
The alkoxy group includes, for example, alkoxy groups of 10 or less carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, heptoxy, octoxy, etc. Preferable examples of the alkoxy group are methoxy, ethoxy and isopropoxy.
The lower alkoxy group includes, for example, alkoxy groups of 6 or less carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. Especially preferable examples of the lower alkoxy group are methoxy, ethoxy and isopropoxy.
The alkylthio group includes, for example, alkylthio groups of 10 or less carbon atoms, such as methylthio, ethylthio, propylthio, butylthio, isopropylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, heptylthio, octylthio, etc.
The lower alkyltho group includes, for example, alkylthio groups of 6 or less carbon atoms, such as methylthio group, ethylthio group, etc.
The substituent(s) of each of the substituted alkoxy group, the substituted lower alkoxy group and the substituted alkylthio group includes, for example, halogen atoms (which may be present on the same carbon atom in a number of 1 to 3 as the substituent(s)), hydroxyl group, alkoxy groups, aryl groups (e.g. phenyl group), substituted aryl groups and cycloalkyl groups.
The aryl group includes, for example, aryl groups of 10 or less carbon atoms, such as phenyl, naphthyl, etc.
The cycloalkyl group includes, for example, cycloalkyl groups of 8 or less carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
As the substituent of the xe2x80x9csubstituted aryl groupxe2x80x9d as
1) the substituent of the substituted alkyl group,
2) the substituent of the substituted lower alkyl group,
3) the substituent of the substituted alkoxy group,
4) the substituent of the substituted lower alkoxy group, and
5) the substituent of the substituted alkylthio group,
there are exemplified lower alkyl groups; substituted lower alkyl groups (whose substituent(s) may be selected from halogen atoms (which may be present on the same carbon atom in a number of 1 to 3 as the substituent(s)), hydroxyl group, alkoxy groups, phenoxy group and cycloalkyl groups); halogen atoms, hydroxyl group and lower alkoxy groups.
The substituent R3 includes, for example, lower alkyl groups and halogen atoms.
Each of the substituents R5 and R6 includes, for example, lower alkyl groups, hydroxyl group, acyloxy groups, alkoxy groups and halogen atoms. Alternatively, R5 and R6 may bind to each other to form a 3- to 8-membered cycloalkane ring together with the carbon atom to which they are bonded.
The acyloxy groups include, for example, alkanoyloxy groups, substituted alkanoyloxy groups, aroyloxy groups and substituted aroyloxy groups.
The alkanoyloxy groups include, for example, alkanoyloxy groups 7 or less carbon atoms, such as acetyloxy, propionyloxy, etc.
The substituent(s) of the substituted alkanoyloxy group includes, for example, halogen atoms (which may be present on the same carbon atom in a number of 1 to 3 as the substituent(s)), hydroxyl group and alkoxy groups.
The aroyloxy groups include, for example, aroyloxy groups of 11 or less carbon atoms, such as benzoyloxy, naphthoyloxy, etc.
The substituent(s) of the substituted aroyloxy group includes, for example, halogen atoms, lower alkyl groups, hydroxyl group, lower alkoxy groups and substituted carbamoyl groups. The two adjacent substituents of the substituted aroyloxy group selected from the above-exemplified substituents may bind to each other to form a bicyclic substituted aroyloxy group such as a group represented by any of the formulas: 
wherein R7 is a hydrogen atom, a lower alkyl group, a benzyl group or a protective group for the nitrogen atom.
The aromatic heterocyclic group includes, for example, 5- or 6-membered aromatic heterocyclic groups containing 1 to 3 heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom. More specific examples thereof are pyridyl (whose nitrogen atom may be an oxidized one), thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazyl, pyrimidyl, pyridazyl, oxazolyl, thiazolyl, oxadiazolyl, triazolyl and tetrazolyl.
The aromatic heterocyclic group may form a fused ring together with another ring. Such xe2x80x9canother ringxe2x80x9d includes hydrocarbon rings and heterocyclic rings. The hydrocarbon rings include, for example, benzene ring and aliphatic hydrocarbon rings (e.g. 5- or 6-membered saturated or unsaturated aliphatic hydrocarbon rings). The heterocyclic rings include, for example, saturated or unsaturated aliphatic heterocyclic rings or aromatic heterocyclic rings, which are 5- or 6-membered heterocyclic rings containing 1 to 3 heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom. Specific examples of such a fused heterocyclic ring group are quinolyl, benzofuranyl, quinazolyl, benzothienyl and groups represented by the following formulas: 
wherein the ring N is a 5- to 8-membered ring containing a nitrogen atom in the ring.
As
1) the substituent(s) of the xe2x80x9csubstituted aryl group for Zxe2x80x9d and
2) the substituent(s) of the substituted aromatic heterocyclic group,
there are exemplified lower alkyl groups, substituted lower alkyl groups, lower alkoxy groups, substituted lower alkoxy groups, carbamoyl group, N-substituted carbamoyl groups, N,N-di-substituted carbamoyl groups, alkoxycarbonyl groups, formyl group, acyl groups, cyano group, halogen atoms, lower alkylthio groups, lower alkanesulfonyl groups, lower alkanesulfonyl amide groups, lower alkylureide groups, phenylureide groups, benzylureide groups, amino group, lower alkylamino groups, lower alkanoylamino groups, aroylamino groups, hydroxyl group, lower alkanesulfonyloxy groups, oxime groups, oxime ether groups, cycloalkyl groups, aryl groups, substituted aryl groups, aromatic heterocyclic groups, substituted aromatic heterocyclic groups, aminosulfonyl group and lower alkylaminosulfonyl groups. The two adjacent substituents of the substituted aryl group or substituted aromatic heterocyclic group selected from the above-exemplified substituents may bind to each other to form a ring. For example, the substituted aryl groups include, for example, groups represented by any of the following formulas: 
wherein R7 is a hydrogen atom, a lower alkyl group, a benzyl group or a protective group for the nitrogen atom. When two or more substituents are present in the substituted aryl group or substituted aromatic heterocyclic group, they may be independently selected from the above-exemplified groups.
The aliphatic heterocyclic group having an amide linkage or an imide linkage in the ring includes, for example, 5- or 6-membered heterocyclic groups such as 5- or 6-membered cyclic imide groups or cyclic amide groups, for example, succinimide group and glutarimide group. In addition, said aliphatic heterocyclic group includes, for example, groups represented by the formulas: 
Said aliphatic heterocyclic group may be a ring fused with another ring. Such xe2x80x9canother ringxe2x80x9d includes hydrocarbon rings and heterocyclic rings. The hydrocarbon rings include, for example, benzene ring and aliphatic hydrocarbon rings (e.g. 5- or 6-membered saturated or unsaturated aliphatic hydrocarbon rings). The heterocyclic rings include, for example, saturated or unsaturated aliphatic heterocyclic rings or aromatic heterocyclic rings, which are 5- or 6-membered heterocyclic rings containing 1 to 3 heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom. Such a fused ring group includes, for example, groups represented by the formulas: 
wherein the bond indicated by a solid line and a dotted line is either a single bond or a double bond, E is xe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94, and R is a hydrogen atom, a lower alkyl group, a benzyl group, a protective group for the nitrogen atom, or the substituted lower alkyl group defined above.
The above-mentioned aliphatic heterocyclic group having an amide linkage or an imide linkage in the ring may have a substituent(s). The substituent(s) includes, for example, lower alkyl groups, substituted lower alkyl groups, lower alkoxy groups, hydroxyl group, oxo group, aryl groups and halogen atoms. When two or more substituents are present in said aliphatic heterocyclic group, they may be independently selected from the above-exemplified groups.
The substituent(s) of each of the N-substituted carbamoyl group and the N,N-di-substituted carbamoyl group includes, for example, lower alkyl groups, substituted lower alkyl groups, aryl groups, hydroxyl group and lower alkoxy groups. Alternatively, the two substituents of the N,N-di-substituted carbamoyl group may bind to each other to form a cyclic group such as a piperidino group or a benzopiperidino group (e.g. a group represented by the formula: 
together with the nitrogen atom to which they are bonded.
The alkoxycarbonyl groups include, for example, alkoxycarbonyl groups of 7 or less carbon atoms, such as methoxycarbonyl group, ethoxycarbonyl group, etc.
The acyl groups include, for example, alkanoyl groups, substituted alkanoyl groups, aroyl groups and substituted aroyl groups.
The alkanoyl groups include alkanoyl groups of 7 or less carbon atoms, such as acetyl, propionyl, etc.
The substituent(s) of the substituted alkanoyl group includes, for example, halogen atoms (which may be present on the same carbon atom in a number of 1 to 3 as the substituent(s)), hydroxyl group and alkoxy groups.
The aroyl groups include, for example, aroyl groups of 11 or less carbon atoms, such as benzoyl, naphthoyl, etc.
The substituent(s) of the substituted aroyl group includes, for example, halogen atoms, lower alkyl groups, hydroxyl group, lower alkoxy groups and substituted carbamoyl groups. The two adjacent substituents of the substituted aroyl group selected from the above-exemplified substituents may bind to each other to form a bicyclic substituted aroyl group such as a group represented by any of the following formulas: 
wherein R7 is a hydrogen atom, a lower alkyl group, a benzyl group or a protective group for the nitrogen atom.
The lower alkanesulfonyl groups include, for example, alkanesulfonyl groups of 6 or less carbon atoms, such as methanesulfonyl group, ethanesulfonyl group, etc.
The lower alkanesulfonyl amide groups include, for example, alkanesulfonyl amide groups of 6 or less carbon atoms, such as methanesulfonyl amide group, ethanesulfonyl amide group, etc.
The lower alkylureide groups include, for example, alkylureide groups of 6 or less carbon atoms, such as methylureide group, ethylureide group, etc.
The lower alkylamino groups include, for example, mono- or di-alkylamino groups of 6 or less carbon atoms, such as methylamino group, ethylamino group, dimethylamino group, etc.
The lower alkanoylamino groups include, for example, alkanoylamino groups of 7 or less carbon atoms, such as acetylamino group, propionylamino group, etc.
The aroylamino groups include, for example, aroylamino groups of 11 or less carbon atoms, such as benzoylamino group, naphthoylamino group, etc.
The lower alkanesulfonyloxy groups include, for example, alkanesulfonyloxy groups of 6 or less carbon atoms, such as methanesulfonyloxy group, ethanesulfonyloxy group, etc.
The oxime groups include, for example, oximes of alkanoyl groups of 6 or less carbon atoms, such as 1-hydroxyiminoethyl group, 1-hydroxyiminopropyl group, etc.
The oxime ether groups include, for example, oxime ether groups formed by an alkanoyl group of 6 or less carbon atoms and an alkyl group of 6 or less carbon atoms, such as 1-methoxyiminoethyl group, 1-ethoxyiminoethyl group, 1-methoxyiminopropyl group, 1-ethoxyiminopropyl group, etc.
As the substituent(s) of each of
1) the xe2x80x9csubstituted aryl groupxe2x80x9d as
i) the substituent(s) of the xe2x80x9csubstituted aryl group for Zxe2x80x9d, and
ii) the substituent(s) of the substituted aromatic heterocyclic group; and
2) the xe2x80x9csubstituted aromatic heterocyclic groupxe2x80x9d as
i) the substituent(s) of the xe2x80x9csubstituted aryl group for Zxe2x80x9d, and
ii) the substituent(s) of the substituted aromatic heterocyclic group,
there are exemplified lower alkyl groups, substituted lower alkyl groups, halogen atoms, hydroxyl group and lower alkoxy groups. When two or more substituents are present as said substituent(s), they may be independently selected from the above-exemplified groups.
The lower alkylaminosulfonyl groups include, for example, alkylaminosulfonyl groups of 6 or less carbon atoms, such as methylaminosulfonyl group, ethylaminosulfonyl group, dimethylaminosulfonyl group, etc.
The term xe2x80x9cprodrugxe2x80x9d used herein means a derivative that is decomposed in a living body by acid hydrolysis or enzymatically to give a compound of the above formula (1). For example, when the compound of the formula (1) has a hydroxyl group or an amino group, the prodrug may be produced by modifying such a group according to a conventional method.
The starting compounds (2), (3), (4), (5), (6), (7), (8), (9), (10) and (11) described hereinafter, some of which are novel, may be produced by the processes described in the working examples described hereinafter, the same processes as these processes, or conventional processes.
A desired compound (1) or a salt thereof may be produced by any of the processes shown in the following schemes.
Production Process 1 (Alkylation of an Amino Group) 
wherein R0, R3, Y, Z and n are as defined above, and X is a leaving group.
The leaving group X includes, for example, halogen atoms such as chlorine atom, bromine atom, iodine atom, etc.; and acyloxy groups such as acetoxy, tosyloxy, mesyloxy, etc.
A desired compound (1) or a salt thereof may be obtained by reacting a compound (2) or a salt thereof with a compound (3) or a salt thereof. The reaction may be carried out for 10 minutes to 48 hours in a suitable inert solvent at a temperature in a range of about xe2x88x9220xc2x0 C. to the boiling point of the solvent used, optionally in the presence of a base and optionally in the presence of a phase transfer catalyst.
The base includes, for example, organic bases such as triethylamine, pyridine, etc.; inorganic bases such as potassium carbonate, sodium hydroxide, sodium hydride, etc.; and metal alkoxides such as sodium methoxide, potassium tert-butoxide, etc.
The phase transfer catalyst includes, for example, tetrabutylammonium hydrogensulfate.
The inert solvent includes, for example, acetonitrile; halogenated hydrocarbons such as chloroform, dichloromethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, etc.; lower alcohols such as methanol, ethanol, isopropanol, etc.; aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc.; and mixed solvents thereof.
Production Process 2 (Reduction of an Amide: when Y is a Group Represented by xe2x80x94CH2xe2x80x94Y1xe2x80x94) 
wherein R0, R3, Z and n are as defined above, Y1 is a lower alkylene or a substituted lower alkylene, and xe2x80x94CH2xe2x80x94Y1xe2x80x94 corresponds to the above symbol Y.
An intermediate (5) may be produced by reacting a compound (2) or a salt thereof with a compound (4) or a salt thereof to form an amide linkage. This amide linkage formation reaction may be carried out by adopting a conventional method such as an acid chloride method using thionyl chloride, oxalyl chloride or the like; a mixed acid anhydride method using a chlorocarbonic acid ester or the like; or a method using a condensing agent such as dicyclohexyl-carbodiimide, carbonyldiimidazole or the like.
A compound (1a) may be obtained by reacting the intermediate (5) for 10 minutes to 48 hours by the use of a suitable reducing agent (e.g. aluminum lithium hydride, sodium tetrahydroborate or diborane) in a suitable inert solvent (e.g. an ether solvent such as diethyl ether, tetrahydrofuran (THF) or 1,4-dioxane) at a temperature in a range of about xe2x88x9220xc2x0 C. to the boiling point of the solvent used. More specifically, the compound (1a) may be obtained by carrying out the reduction reaction for 20 minutes to 1 hour by the use of diborane in tetrahydrofuran (THF) under ice-cooling or at room temperature.
Production Process 3 (Reductive Amination: when Y is a Group Represented by xe2x80x94CH2xe2x80x94Y1xe2x80x94) 
wherein R0, R3, Y1, Z and n are as defined above.
A desired compound (1a) or a salt thereof may be obtained by reacting a compound (2) or a salt thereof with a compound (6) or a salt thereof under reductive amination conditions. As a reducing agent, sodium cyanoborohydride and sodium borohydride may be used. The compound (2) and the compound (6) may be mixed as they are or may be reacted after previous formation of an imine. The reaction may be carried out for 10 minutes to 48 hours in a suitable inert solvent (e.g. acetonitrile; a halogenated hydrocarbon such as chloroform, dichloromethane or the like; an aromatic hydrocarbon such as benzene, toluene or the like; an ether solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane or the like; a lower alcohol such as methanol, ethanol, isopropanol or the like; an aprotic polar solvent such as dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide or the like; or a mixed solvent thereof) at a temperature in a range of about xe2x88x9220xc2x0 C. to the boiling point of the solvent used.
Production Process of a Compound (2a)
A compound (2a) or a salt thereof, which is useful as an intermediate, may be produced by the process shown in the following scheme. The compound (2) may be produced in the same manner as shown therein. 
wherein R1, R2, R3 and n are as defined above, PG is a protective group for the nitrogen atom, and X1 is a leaving group.
The protective group for the nitrogen atom includes, for example, alkyloxycarbonyl groups such as t-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, etc. The leaving group X1 includes, for example, halogen atoms such as chlorine, bromine, iodine, etc.; and acyloxy groups such as acetoxy, tosyloxy, mesyloxy, etc.
A compound (7) is converted to a Wittig-Horner reagent (8). This conversion may be carried out by reacting with triethyl phosphite for 1 hour to 3 days without solvent or in an inert solvent at a temperature in a range of ice-cooling to the boiling point of the solvent used or triethyl phosphite. The Wittig-Horner reagent (8) may be converted to a compound (10) by reacting with a ketone (9) for 10 minutes to 48 hours in a suitable inert solvent in the presence of a base at a temperature of about xe2x88x9220xc2x0 C. to the boiling point of the solvent used.
The base includes, for example, organic bases such as triethylamine, pyridine, etc.; inorganic bases such as potassium carbonate, sodium hydroxide, sodium hydride, etc.; and metal alkoxides such as sodium methoxide, potassium tert-butoxide, etc.
The inert solvent includes, for example, acetonitrile; halogenated hydrocarbons such as chloroform, dichloromethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; lower alcohols such as methanol, ethanol, isopropanol, etc.; aprotic polar solvents such as dimethylformamide, N-methyl-pyrrolidone, dimethyl sulfoxide, etc.; and mixed solvents thereof.
More preferably, the latter conversion may be carried out by conducting the reaction for 1 to 5 hours at 0xc2x0 C. to 50xc2x0 C. by using an inorganic base such as sodium hydride as the base and an ether solvent such as 2-dimethoxyethane as the inert solvent.
The compound (10) may be converted to a compound (11) by catalytic hydrogenation. When R1 or R2 is a bromine atom, this conversion may be carried out by conducting the reduction reaction at 0xc2x0 C. to 50xc2x0 C. by the use of a rhodium catalyst (e.g. rhodium-carbon) as a catalyst for the hydrogenation. The desired compound (2a) may be obtained by subjecting the compound (11) to deprotection by a conventional method.
Throughout the present description, amino acids, peptides, protective groups, condensing agents and the like are indicated in some cases with abbreviations according to IUPAC-IUB (the committee for biochemical nomenclature) which are conventionally used in the art.
Suitable salts and pharmaceutically acceptable salts of the starting compounds and the desired compounds are conventional nontoxic salts. Those skilled in the art may properly select such salts from, for example, acid addition salts including organic acid salts (e.g. acetic acid salt, trifluoroacetic acid salt, maleic acid salt, fumaric acid salt, citric acid salt, tartaric acid salt, methanesulfonic acid salt, benzenesulfonic acid salt, formic acid salt and toluenesulfonic acid salt) and inorganic acid salts (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate and phosphate); salts with amino acids (e.g. arginine, aspartic acid and glutamic acid); metal salts including alkali metal salts (e.g. sodium salt and potassium salt) and alkaline earth metal salts (e.g. calcium salt and magnesium salt); ammonium salts; and organic base salts (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt and N,Nxe2x80x2-dibenzylethylenediamine salt).
In any of the production processes explained above, when any functional group in a site other than a reaction site changes under the reaction conditions explained above or is unsuitable for practicing the explained process, the desired compound may be obtained by protecting the functional group at the site other than the reaction site, and carrying out the reaction, followed by deprotection. As a protective group, there may be used conventional protective groups such as those described, for example, in Green (T.W./), Protective Groups in Organic Synthesis, John Wiley and Sons Inc. (1981). More specifically, a protective group for an amine includes ethoxycarbonyl, t-butoxycarbonyl, acetyl, benzyl, etc., and a protective group for a hydroxyl group includes trialkylsilyl, acetyl, benzyl, etc.
The introduction and removal of the protective group may be carried out by a method conventionally adopted in organic synthetic chemistry [see, for example, the above reference Protective Groups in Organic Synthesis] or a method according thereto.
A compound of the above formula (1) or (1a) may be converted to another compound of the formula (1) or (1a), respectively, by converting its functional group properly. The functional group may be converted by a conventional method [see, for example, R. C. Larock, Comprehensive Organic Transformation (1989)].
The intermediate(s) and desired compound in each of the production processes described above may be isolated and purified by purification methods conventionally adopted in organic synthetic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatographies, etc. The intermediate(s) may be subjected to the subsequent reaction without particular purification.
There are compounds (1) that can have tautomers. The present invention includes all possible isomers and mixtures thereof, inclusive of the tautomers. When a salt of a compound (1) is desired, it is obtained as follows. When the compound (1) is obtained in the form of a salt, it is sufficient that the salt is purified as it is. When the compound (1) is obtained in a free form, it is sufficient that the compound (1) is dissolved or suspended in a suitable organic solvent and allowed to form a salt by a conventional method by addition of an acid and a base. Each of a compound (1) and a pharmacologically acceptable salt thereof exists in the form of an adduct with water or any of various solvents in some cases. The present invention also includes such an adduct. A compound (1) and the other compounds can have one or more stereoisomers due to an asymmetric carbon atom(s). The present invention includes all of these isomers and mixtures thereof.
A desired compound (1) and a pharmaceutically acceptable salt thereof have pharmacological effects such as SRI (serotonin reuptake inhibition) effect. Therefore, they are useful for treating or preventing diseases in which the serotonin nervous system participates, for example, mood disorders including depression, seasonal affective disorder and dysthymia; anxiety disorders including obsessive-compulsive disorder and panic disorder; agoraphobia and avoidant personality disorder; social phobia; compulsive reaction; post-traumatic stress disorder; and psychosomatic disorder. Moreover, the desired compound (1) and pharmaceutically acceptable salt thereof of the present invention are useful also for treating or preventing retention defects including dementia, forgetfulness and retention defect associated with aging; eating disorders including anorexia nervosa and bulimia nervosa; obesity; somnipathy; schizophrenia; chemical dependency due to alcohol, tobacco, nicotine or the like; cluster headache; migraine; pains; Alzheimer""s disease; chronic paroxysmal migraine; headache associated with vasculopathy; Parkinson""s disease including dementia, depression and anxiety caused by Parkinson""s disease, Parkinsonism induced by a neuroleptic agent, and tardive dyskinesia; and the like.
Furthermore, the desired compound (1) and pharmaceutically acceptable salt thereof of the present invention are useful for treating or preventing dysendocrinism such as hyperprolactinemia; vasospasm (in particular, cerebrovascular spasm); hypertension; kinetic gastrointestinal troubles and gastrointestinal troubles in which a secretion change participates; sexual dysfunction including premature ejaculation; drug dependence; and the like.
For medical purposes, the compound (1) and pharmaceutically acceptable salt thereof of the present invention may be used in the form of a pharmaceutical composition as a mixture with a pharmaceutically acceptable carrier (e.g. a solid or liquid and organic or inorganic excipient) which is suitable for oral or parenteral administration or external use which include local, enteral, intravenous, intramuscular, inhalational, nasal, intra-articular, intra-spinal, transtracheal and transorbital administrations. The pharmaceutical composition includes solids, semisolids and liquids, such as capsules, tablets, pellets, sugar-coated tablets, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, poultices, gels, tapes, ophthalmic solutions, solutions, syrups, aerosols, suspensions, emulsions, etc. These pharmaceutical compositions may be prepared by conventional processes. If desired, conventional additives such as an assistant, stabilizer, wetting agent, emulsifier, buffer, etc. may be incorporated into the pharmaceutical compositions.
Although the dose of the compound (1) is varied depending on the age and condition of a patient, average doses of the compound (1) per administration of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg are effective against diseases such as mood disorders including depression, seasonal affective disorder and dysthymia; and anxiety including generalized anxiety disorder and panic disorder. In general, when administered to human beings, the compound (1) may be administered in a dose of 0.1 mg/individual to about 1,000 mg/individual per day, preferably 1 mg/individual to about 100 mg/individual per day.